Second of Three Pivotal Phase Three Bone Metastases Trials Meets Primary Endpoint Denosumab Delayed Time to Skeletal Related Events

THOUSAND OAKS, Calif., Aug. 3 /PRNewswire-FirstCall/ -- Amgen (Nasdaq: AMGN) today announced positive top-line results from a pivotal Phase 3 head-to-head trial evaluating denosumab administered subcutaneously versus Zometa (zoledronic acid) administered as an intravenous (IV) infusion in the treatment of bone metastases in 1,776 advanced cancer patients with solid tumors (not including breast and prostate cancer) or multiple myeloma.

For the primary endpoint, patients treated with denosumab experienced a similar time to first skeletal-related event (SRE) (fracture, radiation to bone, surgery to bone, or spinal cord compression) compared with those receiving Zometa (hazard ratio 0.84, 95 percent CI: 0.71-0.98), which is statistically significant for non-inferiority (p<0.0007). Although numerically greater, the delay in the time to first SRE associated with denosumab treatment was not statistically superior compared to Zometa (adjusted p=0.06) (secondary endpoint). The time to first-and-subsequent SRE was also numerically greater but not statistically superior compared to Zometa (hazard ratio 0.90, 95 percent CI: 0.77-1.04) (secondary endpoint).

Overall, the incidence of adverse events and serious adverse events was consistent with what has previously been reported for these two agents. Rates of osteonecrosis of the jaw (ONJ) were balanced and infrequent in both treatment groups (10 patients receiving denosumab as compared with 11 patients receiving Zometa). Infectious adverse events were balanced between the two treatment arms, as was overall survival and the time to cancer progression.

"We are extremely pleased with these results, which continue to demonstrate that inhibiting RANK Ligand with denosumab provides a clinically meaningful benefit for advanced cancer patients with solid tumors that have metastasized to the bone, and to patients with multiple myeloma, both groups who routinely suffer SREs," said Roger M. Perlmutter, M.D., Ph.D., executive vice president of Research and Development at Amgen. "We are very encouraged by the overall strength of the data, which we will present in a scientific forum later this year. We are also looking forward to reviewing the results of a final SRE study, in patients with advanced prostate cancer, next year."

Bone metastases, the spread of tumors to the bone, are a serious concern for many advanced cancer patients. When cancer spreads to the bone, the growing cancer cells weaken and destroy the bone around the tumor. This damage can result in a number of serious bone complications, collectively called SREs.

Full safety and efficacy data will be submitted for presentation at an upcoming medical meeting in the second half of this year.

Study Design

This was an international Phase 3, randomized, doubleblind, active controlled study comparing denosumab with Zometa in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. Patients enrolled in this event-driven study were randomized in a one-to-one ratio to receive either 120 mg of denosumab subcutaneously every four weeks (Q4W) or Zometa administered intravenously at a dose of 4 mg single, 15 minute infusion every four weeks.

In clinical trials thus far to test new medications for bone metastases, treatment success has been measured by whether the bone complications, or SREs, caused by the tumor are reduced or delayed. The primary and secondary endpoints of the denosumab bone metastases studies use a composite endpoint of four SREs - fracture, radiation to bone, surgery to bone, and spinal cord compression - to measure the effectiveness of denosumab versus Zometa.

The primary endpoint was to evaluate if denosumab is non-inferior to Zometa with respect to the first on-study SRE in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma and bone metastases. Secondary endpoints were to evaluate if denosumab is superior to Zometa with respect to the first on-study SRE, as well as first-and-subsequent on-study SREs, and to assess the safety and tolerability of denosumab compared with Zometa.

About Denosumab and Amgen's Research in Bone Biology

Denosumab is the first fully human monoclonal antibody in late stage clinical development that specifically targets RANK Ligand, the essential regulator of osteoclasts (the cells that break down bone). With more than 19,000 patients in trials across indications worldwide, the denosumab development program is the largest ever initiated by Amgen. This broad and deep development program demonstrates Amgen's commitment to researching and delivering pioneering medicines to patients with unmet medical needs. Amgen is studying denosumab in numerous tumor types across the spectrum of cancer induced bone disease. Over 11,000 patients have been enrolled in the denosumab oncology clinical trials testing the drug for bone loss and destruction associated with cancer treatment-induced bone loss in breast and prostate cancers, for the prevention of skeletal related events due to the spread of cancer to the bone in multiple myeloma and multiple solid tumors, and for its potential to delay bone metastases in prostate cancer.

Bone Metastases: Impact and Prevalence

Bone metastases, cancer cells that separate from tumors and migrate to bone tissue where they settle and grow, occur in more than 1.5 million people worldwide.(1) With improvements in cancer care, including earlier diagnosis and new treatment options, leading to increases in survival rates(2), the number of patients developing metastatic disease secondary to a primary cancer is increasing. Bone metastases are a significant problem for patients with certain types of advanced cancer, with incidence rates of nearly 100 percent in myeloma patients and as high as 75 percent in solid tumor patients.

With bone metastases the growing cancer cells weaken and destroy the bone around the tumor. The damage the tumor has caused to the bone can result in a number of serious complications, collectively called skeletal related events (SREs). These include fracture of a bone, radiation to bone, surgery to bone, or spinal cord compression. All are serious complications for advanced cancer patients.

Regardless of the type of underlying cancer, the process by which cancers invade and destroy bones is fundamentally the same. At the center of this destructive process is a protein RANK Ligand that is stimulated by the presence of cancer in the bone.

The economic burden of U.S. patients with bone metastases is significant and was estimated to be $12.6 billion last year.(3) Patients with bone metastases who experience an SRE incur significantly higher medical costs compared with those who do not experience an SRE.(4)

About Amgen

Amgen discovers, develops and delivers innovative human therapeutics. A biotechnology pioneer since 1980, Amgen was one of the first companies to realize the new science's promise by bringing safe and effective medicines from lab, to manufacturing plant, to patient. Amgen therapeutics have changed the practice of medicine, helping millions of people around the world in the fight against cancer, kidney disease, rheumatoid arthritis, and other serious illnesses. With a deep and broad pipeline of potential new medicines, Amgen remains committed to advancing science to dramatically improve people's lives. To learn more about our pioneering science and our vital medicines, visit www.amgen.com.

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ZOMETA is a registered trademark of Novartis Oncology.

*Editors Note: The FDA has provisionally approved the trade name Prolia(TM) for the proposed indications of treatment and prevention of osteoporosis in postmenopausal women, and treatment and prevention of bone loss in patients undergoing hormone ablation for prostate or breast cancer. The Prolia(TM) trade name is only for these indications and may not apply for other indications of denosumab.

(1) Capanna R, Coia LR, Coleman R. et al. eds. Textbook of Bone Metastases. Hoboken, NJ: Edition: John Wiley and Sons; 2005:105.

(2) Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer. 2002 Aug;2(8):584-93.

(3) Schulman K and Kohles J. Cancer. 2007;109:2334-2342

(4) GVD/Barber ISPOR 2008 Poster; Schulman 2007; Delea et al. 2006

Amgen, Thousand Oaks
Lisa Rooney, 805-447-6437 (media)
Arvind Sood, 805-447-1060 (investors)

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SOURCE Amgen